Rapidly disintegrating methylcellulose tablets

ABSTRACT

The present invention relates to a novel pharmaceutical composition and process for preparing swallowable methylcellulose tablets that disintegrate rapidly and meet USP disintegration standards in 0.1N hydrochloric acid as well as water.

This application is a 371 of PCT/US98/17440 filed Aug. 21, 1998 whichclaims benefit of No. 60/056,899 filed Aug. 22, 1997 which claimsbenefit of No. 60/081,644 filed Apr. 14, 1998.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparingcompressed methylcellulose containing tablets which meet USPdisintegration standards.

BACKGROUND OF THE INVENTION

The history of cellulose ethers, such as methylcellulose andcarboxymethyl-cellulose, supports that these agents have effectivenessas bulk laxatives. Their mechanism of action involves increasing boththe water content of, and the bulk content of the stool, as well aslubricating the stool; thereby relieving constipation.

Cellulose ethers have been administered as bulk laxatives in dosageforms comprising of tablets, suspensions, and bulk powders; the latteras sugar-free or in compositions containing high amounts of sugar.

Cellulose ethers administered as suspensions in water may contain highconcentrations of sucrose or other sugars and flavors. In suchformulations, the sugar competes with the cellulose ether for availablewater, thereby preventing the cellulose ether from hydratingsufficiently to form a gel. The advantages of using a suspensionformulation is that the cellulose either is dispersed sufficiently toavoid any significant lumping in the digestive tract. However, thesuspensions are viscous, semi-gelatinous, and visually unappealing tothe consumer. Another disadvantage is the unpalatability of thesuspensions due to the slimy mouth feel and extreme sweetness of suchsuspensions. Hence, these dosage forms have not gained significantcustomer acceptance.

Bulk powders of cellulose ethers often exhibit lumping of individualparticles and gelatin and thus, remain undissolved as they pass throughthe digestive tract. That the products are undissolved means that thiswill prevent hydration and gelling of the powder and does not provideefficacy. Additionally, administration of bulk powders has causedcramping, nausea, and vomiting in some patients. Therefore, bulk powdersare not the preferred dosage form for cellulose ethers.

Palatable and visually appealing bulk powders have, however, beenaccomplished by addition of water or another aqueous liquid to a drypowder mix of a water-soluble cellulose ether and a dispersingagent/sweetening component, typically sugar. This technology isdisclosed in South African patent No. 84,1044, published Sep. 26, 1984.The pitfall with these compositions is that they contain about 400calories of nutritive value per dose, primarily due to the high sugarcontent. This high caloric value is not acceptable to the averageconsumers or to users suffering from blood sugar disorders, includingdiabetics. Elderly people are normally, the common strata of thepopulation that suffers from constipation and the more frequent users oflaxatives, and are also commonly suffering with blood sugar disorders.The consumption of large quantities of sugar could aggravate blood sugardisorders.

Sugar encrusted cellulose ethers have been proposed as alternatives tothe bulk powders containing high amounts of sugar. Such formulationshave 1) less sugar such as natural sugar or combination of sugars suchas sucrose, glucose, fructose or corn syrup solids; 2) lower caloricvalue; and 3) are readily dispersed in cold aqueous liquids.

Citrucel® Orange Flavor, a bulk forming laxative containingmethylcellulose as its active ingredient, was first introduced into themarket in 1986. This product contains 15 g of sucrose in a 19 g adultdose, which corresponds to a 2 g dose of methylcellulose. To decreasethe sugar content of this product, a natural flavored formula lower incaloric value, and containing only 1 g sucrose, was developed andintroduced in 1988. Additional patent protection for this product hasfocused on producing a sugar-free and virtually calorie-free powder. Theproduct has a sugar-free sweetener, a dispersing agent, otherexcipients, and flavoring and was marketed in 1991 as Sugar FreeCitrucel® Orange Flavor.

There still remains a need in the art to develop a rapidlydisintegrating solid dosage form of a bulk agent, preferablymethylcellulose, which is convenient to take and transport, sugar free,and easily administered to the consumer having blood sugar disorders ordiabetics, for instance.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparingmethylcellulose tablets which are readily dispersible and meet UnitedStates Pharmacopoeia standards for disintegration. The methylcelluloseis compressed into tablets which contain a suitable diluent, inpreferred w/w ratios. Preferably the tablets rapidly disintegrate,in-vitro in 0.1N hydrochloric acid and water at 37^(±)0.5° C.

DETAILED DESCRIPTION OF THE INVENTION

There is a common belief that tableted cellulose ethers do not readilydissolve in the digestive tract because these cellulose ethers arehighly hygroscopic. The outer portion of the tablet is said to form agel-like hydrate that prevents the tablet from breaking up and greatlyretards the hydration of the inner portion of the tablet. The presentinvention overcomes this art recognized problem and involves preparationof a novel composition, and process of making, by which a rapidlydisintegrating tablet of methylcellulose is prepared. Preferably, allexcipients employed to prepare the tablets of this invention aresugar-free.

The tablets are prepared by a novel process involving a high-shear wetgranulation method, followed by fluidized bed drying, milling, mixingwith the other ingredients, and compression.

The present invention is to a methylcellulose tablet which comprisesmethylcellulose, at least one diluent or filler, and other suitableexcipents well known to those skilled in the art. In some instances itis recognized that the diluent/filler and the disintegrating agent maybe the same.

The tablet formulations of the present invention are advantageous overother dosage forms of methylcellulose because of their convenience ofadministration and rapid disintegration. This is in contrast to tabletsof methylcellulose, formulated as 100% w/w methylcellulose in a 0.5 gmcaplet which have been found not to disintegrate in 0.1N HCl solution,using a conventional disintegration apparatus even after two hours. Thepresent tablets should disintegrate in 0.1N HCl from about 20 to about30 minutes, preferably from about 10 to about 19 minutes, and morepreferably less than 10 minutes; and in water, the tablets shoulddisintegrate from about 25 to about 30 minutes, preferably from about 15to about 24 minutes, and more preferably less than 15 minutes.

It has been found that low molecular weight (mw) methylcellulose is lesseffective for use as a laxative, and therefore is less desirable for usein a rapidly disintegrating tablet formation. Higher molecular weightmethylcellulose is therefore both desirable and necessary in the presentinvention. The fibers must have a sufficient viscosity to gel and retainwater in the gut to provide the stool bulking and softening for laxationuse.

By using the testing methods for methylcellulose under standardconditions, such as those found in the USP XXII, p. 894, ApparentViscosity method for Methylcellulose, or as discussed in Handbook ofPharmaceutical Excipients, APhA, a preferred methylcellulose for useherein should have a viscosity of >1000 centipoises (cps),preferably >2000 centipoises, more preferably >3000 centipoises, andmost preferably >4000 centipoise. Higher molecular weightmethylcellulose than those described is also desirable, however, thecommerical availability of this grade of methylcellulose being thelimiting feature. At present the upper limit of commercially availablemethylcellulose is about 6000 cps, which is encompassed within the scopeof this invention. One presently available methylcellulose product foruse herein is Methocel A4M, made by Dow Chemical Company, Midland Mich.as Dow Methocel A4M, having a viscosity of about 3000 to about 5,600cps, which is within 75 to 140% of the desired target viscosity herein.

Preferred swellable diluents or fillers for use in this formulationinclude, but are not limited to, various grades of microcrystallinecellulose, such as Avicel PH101, Avicel PH102, & Avicel PH200; Cornstarch; or Starch 1500.

Preferably the diluent is microcrystalline cellulose. A preferred sizeof microcrystalline cellulose is from about 50 to 180 micron, morepreferably about 50. Avicel PH101 has a mean particle size of about 50;Avicel PH 102 has a mean particle size of about 100; and Avicel PH 200has a mean particle size of about 190 microns. Preferably the preferredmicrocrystalline cellulose is Avicel PH 101.

It is noted that the ratio of methylcellulose to diluent will dependupon the diluent chosen, and is within the skill of the art to determinewith preciseness the necessary ratios.

Suitable ratios for particular diluents are described below, however, toprovide greater assistance (in % w/w) ratios:

For Methylcellulose: microcrystalline cellulose, from about 2:1 to about14:1. Preferably for Avicel PH 101 from about 2.2-13.5:1; for Avicel PH102 from about 2.4-8.3:1; and for Avicel PH 200 from about 2.4-4:1.

For Methylcellulose:Corn starch from about 7.5 to about 15, preferablyfrom about 13.5:1; and

For Methylcellulose:Starch 1500, from about 2.0 to about 5.0:1,preferably from about 2.4:1.

In addition to the above noted diluents or fillers, additionalcomponents include but are not limited to, a wetting agent, a(super)disintegrant, a binding agent, dye(s) or colouring agents, andlubricants, are preferably used to prepare a tablet that is wettedreadily, and is rapidly disintegrated in 0.1N hydrochloric acid andwater, the USP test standard test for methylcellulose.

A preferred wetting agent is sodium lauryl sulfate.

A preferred lubricant is magnesium stearate.

A preferred binder is polyvinylpyrrolidone, or PVP, such as Povidone29K/32.

A preferred disintegrating agent is sodium starch glycolate, such asExplotab®.

As various excipients and diluents will be formulated together, and usedin combinations herein, suggested % w/w ratios for various formulationsare presented below:

Methylcellulose:sodium lauryl sulfate (SLS), from about 60 to about170:1, preferably from about 155:1-170:1;

Methylcellulose:Povidone, preferably PVP 29K/32, from about 8 to about22:1, preferably from about 10.4:1-16.7:1;

Methylcellulose:Magnesium stearate from about 50 to about 150;1,preferably from about 58-132:1;

Sodium lauryl sulfate:Explotab:Avicel PH 101®: Povidone 29K/32:Magnesiumstearate include: 0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.66:0.76-1.14

Sodium lauryl sulfate:Explotabl:Avicel PH 102®: Povidone29K/32:Magnesium stearate include:0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.66:0.76-1.14

Sodium lauryl sulfate:Avicel PH 200®: Povidone 29K/32:Magnesium stearateinclude: 0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04

Sodium lauryl sulfate:Explotab®:Corn starch: Povidone 29K/32:Magnesiumstearate include: 0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.68:0.88-0.95

Sodium lauryl sulfate:Explotab®:Starch 1500®: Povidone 29K/32:Magnesiumstearate include: 0.36-0.38:3.66-7.07:24.05-25.89:4.35-4.68:0.88-0.95

Not wishing to be limited to the explicit excipients noted above, thefollowing alternative agents may be used herein.

Alternatives lubricants to magnesium stearate include, but are notlimited to, calcium stearate, sodium stearate, Cab-O-Sil, Syloid,stearic acid and talc.

Alternatives to PVP include but are not limited to, hydroxypropylcellulose, hydroxypropyl methylcellulose, acacia, gelatin, tragacanth,pregelatinized starch and starch.

Alternatives disintegrants to Explotab include but are not limited to,sodium carboxymethyl-cellulose, Ac-di-sol®, carboxymethylcellulose,veegum, alginates, agar, guar, tragacanth, locust bean, karaya, pectin,and crospovidone.

Alternative wetting agents to sodium lauryl sulfate, include but are notlimited to, magnesium lauryl sulfate.

As noted above, all of these formulations can be prepared with andwithout sugar, a sugar-free formulation can also be administered easilyto consumers with blood sugar disorders or to diabetics in need of suchpreparations.

The amount of methylcellulose present in each dose, as well as thenumber of doses of laxitive taken per day, will depend somewhat on theage, sex, size of the patient, severity of the patient's particularproblem, the advice of the treating physician, if any, and theparticular taste and habits of the patient. Accordingly, the tablets ofthis invention are advantageously administered in a single dose whichmay contain as much as 500 to 1000 mg of methyl cellulose tablet, or ina plurality of smaller doses containing as little as 250 mg per tablet.Most preferably, for laxative effect, each tablet will contain about 500mg methylcellulose and the patient may take 1 to 2 tablets per dose. Adosage of 1000 mg should adequately provide optimal laxative efficacy.Therefore, a preferred range of methylcellulose per tablet is optimallyfrom about 450 to 550 mg, preferably about 500 mg; or alternatively fromabout 200 to about 300 mg for a smaller tablet, preferably about 250 mg;or even in increments of about 125 mg tablet, i.e. 75 to 175 mg pertablet.

While preferably the compressed tablets are uncoated, they may, ifdesired, be coated with any suitable coating agent well known in theart. Suitably the coating agents are those used for immediate releasepurposes and will dissolve in the gastric juices. Such coating agentsare well known to those skilled in the art and include, but are notlimited to hydroxypropyl methylcellulose, or methyl cellulose, or 20%w/w Opadry II, orange in water.

As well readily be seen by the working examples, there are variouscombinations of intra and extragranular mixing which are possible usingthe ingredients herein. All are encompassed within the scope of thisinvention. Generally, the high viscosity methylcellulose, such asMethocel A4M, will first be granulated with a binder, such as povidone,a wetting agent, such as sodium lauryl sulfate, and a suitable colouringagent to form the intragranular mixture which is then granulated. Thesegranular components are then admixed with additional wetting agents, anddisintegrating agents and finally blended with lubricant. This finalgranular mixture is then blended and compressed into the tablets of thepresent invention.

Therefore, another aspect of the present invention is a process forpreparing a tablet formulation which process comprises:

a) blending together to form an intragranular mixture high viscositymethylcellulose of >3000 cps; a diluent selected from microcrystallinecellulose, corn starch, or Starch 1500, or a mixture thereof, alubricating agent and optionally a disintegrant; and

b) adding to the mixture of step (a), a PVP aqueous solution, oralternatively spraying the mixture of step (a) with a PVP aqueoussolution; and preparing granulates; and

c) blending together an extragranular mixture of a wetting agent; alubricating agent; a diluent; and a disintegrant, or a mixture thereof;and

d) compacting the granulates of step (b) with the extragranular mixtureof step (c).

Preferably, in this process the extragranular components includesmicrocrystalline cellulose, sodium lauryl sulfate, sodium starchglycolate, and magnesium stearate. Alternatively, the extragranularcomponents are starch, sodium lauryl sulfate, sodium starch glycolate,and magnesium stearate.

Another aspect of this invention is a process for the manufacture of apharmaceutical tablet, which process comprises mixing

a) granulates comprising high viscosity methylcellulose of >3000 cps; adiluent selected from microcrystalline cellulose, corn starch, Starch1500, or mixtures thereof; and optionally together with anintra-granular disintegrant, and/or wetting agent; with

b) an extra-granular disintegrant, and wetting agent, and optionally anextra-granular lubricant and excipient(s); and

c) compressing into a tablet.

Another aspect of the present invention is the method of relievingconstipation by increasing the water content of the stool, or byproviding a lubricating effect on the stool in a mammal in need thereof,which method comprises administering to said mammal, an effective amountof a high viscosity methylcellulose compressed into a tablet with asuitable diluent.

METHODS OF PREPARATION

The following examples illustrates the invention but is not intended tolimit the scope thereof. All parts and percentages are by weight unlessotherwise indicated. The disintegration time of the formulationdescribed in the Tables below were obtained by using a conventionaldisintegration apparatus.

EXAMPLE 1

TABLE I Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 69.35 Avicel PH101 ® 0.0370 5.13Sodium lauryl sulfate 0.0015 0.21 Povidone 29K/32 0.0480 6.66Dye/Coloring Agent 0.0010 0.14 DI water q.s. q.s. Phase B Phase A 0.587581.48 Sodium lauryl sulfate 0.0015 0.21 Avicel PH200 ® 0.1245 17.27Magnesium stearate 0.0075 1.04 TOTAL 0.7210 100.00

The process of preparing the rapidly disintegrating tablet ofmethylcellulose is carried out using specified quantities ofingredients, such as those mentioned in TABLE I above, using thefollowing steps:

1. Preparation of Povidone K29/32 (PVP) Solution

The specified amount of PVP was weighed and added to the weighedquantity of water and stirred till all the PVP was dissolved completely.

2. Preparation of Phase A

Accurately weighed amounts of Methocel A4M, sodium lauryl sulfate,Avicel PH101, and a colouring agent, such as any suitable FD&C Aluminumlake, were transferred to a Key Hi-shear granulator and mixed for about10 minutes with impellor speed at 135 rpm and chopper speed at 10%. ThePVP solution was sprayed onto the mixture in the granulator at a rate ofapprox. >200 mL/min. Once addition of PVP solution was complete, thechopper was stopped. The mixing was continued in the granulator tillresistance reads about 130-135 watts and the time noted to reach thatwattage. A sample was withdrawn from the wet granulation to record losson drying (% LOD). The moist granules were dried in the Aeromatic Fluidbed dryer in portions till the % LOD reading approximated 1.0-3.0%. Thetemperature of the air in the fluid bed dryer was maintained in approx.90-95° C. and the sample was found to be dry at an outlet airtemperature of approx. 32-52° C. The dried granules were milled througha 12# screen in the Fitz Mill at a high speed. The granules wereweighted and percent yield calculated. The moisture content was measuredfor the dry granules. A sample from the granules was withdrawn andanalyzed for particle size distribution, bulk and tap density, flowindex, and moisture studies. The granules were weighted and ingredientsof Phase B were calculated based on weight of remaining granules.

3. Preparation of the Final Blend

To the weighed milled granules produced in Phase A above, specifiedamounts of sodium lauryl sulfate, and Avicel PH200 were added into theV-blender and mixed about 10 minutes. Magnesium stearate was then addedto the blend and mixed for an additional 3 minutes or so. Samples fromdifferent sections of the V-blender were drawn and submitted foranalyzing blend uniformity. A sample from the final blend was analyzedfor particle size distribution, bulk and tap density, flow index, andmoisture studies. The granules were then weighed.

4. Compression of methylcellulose tablets

The final blend was charged into the hopper of a Stokes signal punch ‘F’tablet press and compressed into caplets with a suitable tooling.

Target tablet hardness desired is between 10 and 25, preferably 8-12SCU; a preferred target weight of each tablet of less than 750 mg; anestimated friability of less than 2.0%, more preferably less than 1.0%,and target disintegration times below 30 minutes in water and acid(shorter disintegration times, less than 10 minutes, more preferablyless than 8 minutes, in 0.1N HCl and less than 15 minutes in water, morepreferably about 8 minutes, are preferred). The tablets were packaged inZiplock bags. The tablets were tested for weight variation, hardness,disintegration in acid and water, friability, moisture (% LOD),thickness, viscosity, and content uniformity.

The formulation in TABLE I exhibited an average disintegration time ofless than 4 minutes in 0.1N HCl and less than 7 minutes in water at37^(±)0.5° C. using the automated disintegration apparatus. Usingconventional disintegration apparatus the formulation of Table I yieldedan average disintegration time of less than 5 minutes in acid and lessthan 9 minutes in water.

EXAMPLE 2

A formulation containing both Avicel PH 101® and Explotab®, intra andextragranularly as shown in TABLE II below, exhibited an averagedisintegration time of less than 1 minute in 0.1N HCl at 37^(±0.5°) C.using the automated disintegration apparatus.

TABLE II Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 60.31 Avicel PH 101 ® 0.0370 4.46Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.46 Explotab ®0.0300 3.62 DI water q.s. q.s. Phase B Phase A 0.6055 73.03 Sodiumlauryl sulfate 0.0017 0.21 Sodium starch glycolate 0.0253 3.05 Avicel PH101 ® 0.1880 22.67 Magnesium stearate 0.0086 1.04 TOTAL 0.8291 100.00

EXAMPLE 3

A formation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and Explotab®, intra and extragranularly, as shown belowin TABLE III exhibited an average disintegration time of less than 3minutes in 0.1N HCl at 37^(±)0.5° C. using the automated disintegrationapparatus.

TABLE III Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 59.24 Avicel PH 101 ®0.0370 4.38 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.03704.38 Explotab ® 0.0300 3.56 Dye/colouring agent 0.0040 0.47 DI waterq.s. q.s. Phase B Phase A 0.6095 72.21 Sodium lauryl sulfate 0.0015 0.18Sodium starch glycolate 0.0220 2.61 Avicel PH 102 ® 0.2035 24.11Magnesium stearate 0.0075 0.89 TOTAL 0.8440 100.00

EXAMPLE 4

A formation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and Explotab® intra and extragranularly as shown in TABLEIV below exhibited an average disintegration time of less than 2 minutesin 0.1N HCl at 37^(±)0.5° C. using the automated disintegrationapparatus.

TABLE IV Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 59.52  Avicel PH 101 ® 0.0370 4.41Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.41 Explotab ®0.0300 3.57 DI water q.s. q.s. Phase B Phase A 0.6055 72.08  Sodiumlauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0220 2.62 Avicel PH102 ® 0.2035 24.23  Magnesium stearate 0.0075 0.89 TOTAL 0.8400 100.00 

In an alternative embodiment of Example 4 above, a coated version of theformulation shown in TABLE IV was tested for disintegration time. Thecoating solution used was 20% w/w Opadry II, Orange in water. Theaverage disintegration time of coated tablets was less than one minutein 0.1N HCl at 37^(±)0.5° C. using the automated disintegrationapparatus.

EXAMPLE 5

A formulation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and Explotab® intra and extragranularly as shown in TABLEV exhibited an average disintegration time of less than one minute in0.1N HCl at 37^(±)0.5° C. using the automated disintegration apparatus.

TABLE V Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 60.24  Avicel PH 101 ® 0.0370 4.46Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.46 Explotab ®0.0300 3.62 DI water q.s. q.s. Phase B Phase A 0.6055 72.95  Sodiumlauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0110 1.33 Avicel PH102 ® 0.2045 24.64  Magnesium stearate 0.0075 0.90 TOTAL 0.8300 100.00 

EXAMPLE 6

A formulation containing Avicel PH101® intragranularly, extragranularAvicel PH 102® and no Explotab® as shown in TABLE VI below, exhibited anaverage disintegration time of less than 3 minutes in 0.1N HCl and lessthan 2 minutes 37^(±)0.5° C. using the automated disintegrationapparatus. The disintegration times using the conventional apparatuswere about 1 minute in acid and less than 2 minutes in water.

TABLE VI Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 67.94  Avicel PH 101 ® 0.0370 5.03Sodium lauryl sulfate 0.0015 0.20 Povidone 29K/32 0.0370 5.03Dye/Colouring Agent 0.0010 0.14 DI water q.s. q.s. Phase B Phase A0.5765 78.34  Sodium lauryl sulfate 0.0011 0.15 Avicel PH 102 ® 0.152720.75  Magnesium stearate 0.0056 0.76 TOTAL 0.7359 100.00 

EXAMPLE 7

A formulation containing corn starch intragranularly, extragranularStarch 1500 and no Explotab® as shown in TABLE VII exhibited an averagedisintegration time of less than 16 minutes in 0.1N HCl at 37^(±)0.5° C.using the automated disintegration apparatus.

TABLE VII Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 63.29  Corn starch 0.03704.68 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/32 0.0370 4.68Dye/Colouring Agent 0.0010 0.13 DI water q.s. q.s. Phase B Phase A0.5765 72.97  Sodium lauryl sulfate 0.0015 0.19 Starch 1500 ® 0.204525.89  Magnesium stearate 0.0075 0.95 TOTAL 0.7900 100.00 

EXAMPLE 8

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intragranular Explotab® as shown in TABLE VIII exhibitedan average disintegration time of less than 14 minutes in 0.1N HCl at37^(±)0.5° C. using the automated disintegration apparatus.

TABLE VIII Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 61.00  Corn starch 0.03704.51 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.51Explotab ® 0.0300 3.66 Dye/Colouring Agent 0.0010 0.12 DI water q.s.q.s. Phase B Phase A 0.6065 73.98  Sodium lauryl sulfate 0.0015 0.18Starch 1500 ® 0.2045 24.93  Magnesium stearate 0.0075 0.91 TOTAL 0.8200100.00 

EXAMPLE 9

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intra as well as extragranular Explotab® as shown inTABLE IX exhibited an average disintegration time of less than 13minutes in 0.1N HCl at 37^(±)0.5° C. using the automated disintegrationapparatus.

TABLE IX Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 59.88  Corn starch 0.0370 4.43Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.43 Explotab ®0.0300 3.59 Dye/Colouring Agent 0.0010 0.12 DI water q.s. q.s. Phase BPhase A 0.6065 72.63  Sodium lauryl sulfate 0.0015 0.18 Starch 1500 ®0.2045 24.49  Explotab ® 0.0150 1.80 Magnesium stearate 0.0075 0.90TOTAL 0.8350 100.00 

EXAMPLE 10

A formulation containing corn starch intragranularly, extragranularStarch 1500 and intra as well as extragranular Explotab® (in higheramounts than shown above in Example 9, TABLE IX) as shown in TABLE Xexhibited an average disintegration time of less than 11 minutes in 0.1NHCl and less than 18 minutes in water at 37³⁵0.5° C. using the automateddisintegration apparatus.

TABLE X Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 58.82  Corn starch 0.0370 4.35Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32 0.0370 4.35 Explotab ®0.0300 3.53 Dye/Colouring Agent 0.0010 0.12 DI water q.s. q.s. Phase BPhase A 0.6065 71.35  Sodium lauryl sulfate 0.0015 0.18 Starch 1500 ®0.2045 24.05  Explotab ® 0.0300 3.54 Magnesium stearate 0.0075 0.88TOTAL 0.8500 100.00 

EXAMPLE 11

Various formulation containing Avicel PH101® intragranularly anddifferent levels of extragranular Avicel PH102® (as shown in Examples11, 12, and 13 below) were made to observe their effect ondisintegration time of the tablets.

The formulation in TABLE XI, below, exhibited an average disintegrationtime of less than one minute in 0.1N HCl and less than 2 minutes inwater at 37^(±)0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 1 minute in bothacid and water.

TABLE XI Swallowable Methylcellulose Tablets Formula Ingredient g/tablet(% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH 101 ® 0.0370  4.62Sodium lauryl sulfate 0.0015  0.19 Povidone 29K/32 0.0480  5.99Dye/Colouring Agent 0.0010  0.12 DI water q.s. q.s. Phase B Phase A0.5875 73.34 Sodium lauryl sulfate 0.0015  0.19 Avicel PH 102 ® 0.204525.53 Magnesium stearate 0.0075  0.94 TOTAL 0.8010 100.00 

EXAMPLE 12

The formulation in TABLE XII exhibited an average disintegration time ofless than 5 minutes in 0.1N HCl and less than 7 minutes in water at37^(±)0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 5 minutes inacid and less than 8 minutes in water.

TABLE XII Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 69.35 Avicel PH 101 ®0.0370  5.13 Sodium lauryl sulfate 0.0015  0.21 Povidone 29K/32 0.0480 6.66 Dye/Colouring Agent 0.0010  0.14 DI water q.s. q.s. Phase B PhaseA 0.5875 81.48 Sodium lauryl sulfate 0.0015  0.21 Avicel PH 102 ® 0.124517.27 Magnesium stearate 0.0075  1.04 TOTAL 0.7210 100.00 

EXAMPLE 13

The formulation in TABLE XIII exhibited an average disintegration timeof less than 10 minutes in 0.1N HCl and less than 14 minutes in water at37^(±)0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 14 minutes inacid and less than 22 minutes in water.

TABLE XIII Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 76.10 Avicel PH 101 ®0.0370  5.63 Sodium lauryl sulfate 0.0015  0.23 Povidone 29K/32 0.0480 7.31 Dye/coloring agent 0.0010  0.15 DI water q.s. q.s. Phase B Phase A0.5875 89.42 Sodium lauryl sulfate 0.0015  0.23 Avicel PH 102 ® 0.0605 9.21 Magnesium stearate 0.0075  1.14 TOTAL 0.6570 100.00 

EXAMPLE 14

The formulation in TABLE XIV exhibited an average disintegration time ofless than 7 minutes in 0.1N HCl and less than 9 minutes in water at37^(±)0.5° C. using the automated disintegration apparatus. Theconventional disintegration apparatus yielded less than 8 minutes inacid and less than 13 minutes in water.

TABLE XIV Swallowable Methylcellulose Tablets Formula Ingredientg/tablet (% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH 101 ®0.0370  4.62 Sodium lauryl sulfate 0.0015  0.19 Povidone 29K/32 0.0480 5.99 Dye/Coloring Agent 0.0010  0.12 DI water q.s. q.s. Phase B Phase A0.5875 73.34 Sodium lauryl sulfate 0.0015  0.19 Avicel PH200 ® 0.204525.53 Magnesium stearate 0.0075  0.94 TOTAL 0.8010 100.00 

All publications, including but not limited to patents and patentapplications cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incoporated by reference herein as thoughfully set forth.

The above description fully disloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A process for preparing a tablet formulationwhich process comprises: a) blending together to form an intragranularmixture high viscosity methylcellulose of >3000 cps; a diluent selectedfrom the group consisting of microcrystalline cellulose, corn starch,pregelatinized starch, and mixtures thereof; and optionally adisintegrant; and b) adding to the mixture of step (a), a PVP aqueoussolution, or alternatively spraying the mixture of step (a) with a PVPaqueous solution; and preparing granulates; and c) blending together anextragranular mixture of a wetting agent; a lubricating agent; andoptionally a disintegrant, or a mixture thereof; and d) compacting thegranulates of step (b) with the extragranular mixture of step (c). 2.The process according to claim 1 wherein the extragranular mixturecomprises microcrystalline cellulose, sodium lauryl sulfate, andmagnesium sterate.
 3. The process according to claim 1 wherein theextragranular mixture comprises starch, sodium lauryl sulfate, sodiumstarch glycolate, and magensium sterate.
 4. A process for themanufacture of a pharmaceutical tablet, which process comprises mixinga) granulates comprising high viscosity methylcellulose of >3000 cps; adiluent selected from the group consisting of microcrystallinecellulose, corn starch, pregelatinized starch, and mixtures thereof; andoptionally an intra-granular disintegrant, and/or a wetting agent; andb) an extra-granular disintegrant, and a wetting agent, and optionallyan extra-granular lubricant; and c) compressing into a tablet.
 5. Theprocess according to claim 1 wherein the extragranular mixture furthercomprises sodium starch glycolate.
 6. The process according to claim 5wherein the sodium starch glycolate is present in an amount of about 3to about 7% w/w.
 7. The process according to claim 1 wherein the diluentof step (a) is microcrystalline cellulose.
 8. The process according toclaim 1 wherein the diluent of step (a) is microcrystalline celluloseand is present in a ratio of methylcellulose to microcrystallinecellulose from about 2.1 to about 14:1.
 9. The process according toclaim 1 wherein the diluent of step (a) is corn starch and is present ina ratio of methylcellulose to cornstarch of from about 7.5 to about15:1.
 10. The process according to claim 1 wherein the diluent of step(a) is pregelatinized starch and is present in a ratio ofmethylcellulose to starch of from about 2.0 to about 5.0:1.